Gadobenic acid

Chemical formula: C₂₂H₂₈GdN₃O₁₁  Molecular mass: 667.73 g/mol  PubChem compound: 131704172

Pharmacodynamic properties

The gadolinium chelate, gadobenate dimeglumine, shortens longitudinal (T1), and transversal (T2) relaxation times of tissue water protons.

The relaxivities of gadobenate dimeglumine in aqueous solution are r1 = 4.39 and r2 = 5.56 mM-1s-1 at 20 MHz.

Gadobenate dimeglumine experiences a strong increase in relaxivity on going from aqueous solution to solutions containing serum proteins, r1 and r2 values were 9.7 and 12.5 respectively in human plasma.

Pharmacokinetic properties

Modelling of the human pharmacokinetics was well described using a biexponential decay model. The apparent distribution and elimination half-times range from 0.085 to 0.117 h and from 1.17 to 1.68 respectively. The apparent total volume of distribution, ranging from 0.170 to 0.248 L/kg body weight, indicates that the compound is distributed in plasma and in the extracellular space.

Gadobenate ion is rapidly cleared from plasma and is eliminated mainly in urine and to a lesser extent in bile. Total plasma clearance, ranging from 0.098 to 0.133 L/h kg body weight, and renal clearance, ranging from 0.082 to 0.104 L/h kg body weight, indicate that the compound is predominantly eliminated by glomerular filtration. Plasma concentration and area under the curve (AUC) values show statistically significant linear dependence on the administered dose. Gadobenate ion is excreted unchanged in urine in amounts corresponding to 78%-94% of the injected dose within 24 hours. Between 2% and 4% of the dose is recovered in the faeces.

Disruption of the blood-brain barrier or abnormal vascularity allows gadobenate ion penetration into the lesion.

Population pharmacokinetic analysis was performed on systemic drug concentration-time data from 80 subjects (40 adult healthy volunteers and 40 paediatric patients) aged 2 to 47 years following intravenous administration of gadobenate dimeglumine. The kinetics of gadolinium down to the age of 2 years could be described by a two compartment model with standard allometric coefficients and a covariate effect of creatinine clearance (reflecting glomerular filtration rate) on gadolinium clearance. The pharmacokinetic parameter values (referenced to adult body weight) were consistent with previously reported values for gadobenic acid and consistent with the physiology presumed to underlie gadobenic acid distribution and elimination: distribution into extracellular fluid (approximately 15 L in an adult, or 0.21 L/kg) and elimination by glomerular filtration (approximately 130 mL plasma per minute in an adult, or 7.8 L/h and 0.11 L/h/kg). Clearance and volume of distribution decreased progressively for younger subjects due to their smaller body size. This effect could largely be accounted for by normalising pharmacokinetic parameters for body weight. Based on this analysis, weight based dosing for gadobenic acid in paediatric patients gives similar systemic exposure (AUC) and maximum concentration (Cmax) to those reported for adults, and confirms that no dose adjustment is necessary for the paediatric population over the proposed age range (2 years and above).

Gadobenic acid is a linear GdCA. Studies have shown that after exposure to GdCAs, gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs, this can cause dosedependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increases and non-clinical data suggest that gadolinium is released from linear GdCAs.

Preclinical safety data

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Indeed, preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Animal experiments revealed a poor local tolerance of gadobenic acid, especially in case of accidental paravenous application where severe local reaction, such as necrosis and eschars, could be observed.

Local tolerance in case of accidental intra-arterial application has not been investigated, so that it is particularly important to ensure that the i.v. needle or cannula is correctly inserted into a vein.

Pregnancy and lactation

In animal studies no untoward effects on the embryonic or foetal development were exerted by daily intravenous administration of gadobenate dimeglumine in rats. Also, no adverse effects on physical and behavioural development were observed in the offspring of rats. However, after repeated daily dosing in rabbit, isolated cases of skeletal variations and two cases of visceral malformations were reported.

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